Medical emulsion lubricant

ABSTRACT

A medical lubricant suitable for injection into the blood stream of a patient. The lubricant is suitable for use with rotating equipment such as atherectomy drive shafts moving within sheaths and over guide wires. The lubricant is an oil-in-water emulsion including a surfactant and a co-surfactant. The lubricant can include a cryogenic agent and a pH buffer and be pH adjusted. One lubricant includes olive oil as an emulsified oil, egg yolk phospholipid as a surfactant, sodium deoxycholate as a co-surfactant, glycerin as a cryogenic agent, L-histidine as a pH buffer, and is pH adjusted using sodium hydroxide. The lubricant can withstand freeze/thaw cycles as well as saline dilution, heating, and shear stress without significant creaming, separation, or unacceptable increases in oil droplet size. Compared to saline, the lubricant provides significantly increased lubrication efficiency for rapidly moving parts.

FIELD OF THE INVENTION

This invention relates to a lubricating composition for use withbiomedical devices. More particularly, this invention relates to aninjectable emulsion capable of being used within human arteries during arotational atherectomy procedure.

BACKGROUND OF THE INVENTION

It is well known that, for various reasons, humans can develop acondition in which a type of plaque or hard deposit builds up along thewalls of the blood vessels, thereby partially blocking the blood flowand causing severe medical conditions. Several different procedures havebeen developed for dealing with this situation. One such procedure isrotational atherectomy, in which a rotary mechanical system removesrelatively hard intravascular deposits from the walls of human arteriesby differentially cutting away the inelastic, hardened deposits whilesparing the soft, elastic tissue of the inner lining of the human bloodvessels. The seminal patent that discloses a device for performing thisprocedure is U.S. Pat. No. 4,990,134 (Auth) entitled "TRANSLUMINALMICRODISSECTION DEVICE", the disclosure of which is incorporated hereinby reference.

In the commercially available device described in U.S. Pat. No.4,990,134, known as the Rotablatorl, an ellipsoidal burr coated withtiny diamond chips is rotated at a speed of at least approximately155,000 revolutions per minute. The burr is connected to a drive motorcapable of high speed rotation via a hollow, flexible, helically-wounddrive shaft, and is routed through the blood vessel over a narrow guidewire that extends through the central bore of the burr and its driveshaft. When this device is operated, the burr preferentially cuts hard,inelastic material (plaque) while sparing soft, elastic material(tissue) and generates microscopic debris fragments that aresufficiently small in size so as to pass through even the narrowestvascular channels (capillary beds) without clogging them.

This Rotablator® atherectomy device, as well as any othermicrodissection device that involves rotational ablation, necessarilygenerates thermal energy during its rotation. For this reason, asdisclosed in U.S. Pat. No. 4,990,134, a biocompatible saline solution isinfused through a plastic sheath within which the drive shaft rotates,to cool the sliding interface during operation.

In addition to performing a cooling function, some lubrication is neededto prevent wear caused by rotational friction between the guide wire andthe drive shaft or between the drive shaft and the plastic sheath. Themajor factors that affect wear in this type of rotational contact areload, temperature, surface speed, surface finish, surface hardness,contact area, time, and the type, amount and viscosity of the lubricant.

During extended operation of the device, however, additional lubricationshould be provided to sustain the performance of the guide wire, thedrive shaft and the sheath. Such a lubricant, if infused through thedevice from outside the patients' body, must of course, be non-toxic andsafe for arterial use. In addition, to be effective in use with theRotablator® advancer/guide wire system, the lubricant should be able towithstand shear stresses at 50° C. and should not promote theagglomeration of ablated plaque particles.

Injectable oil-in-water emulsions are currently being used for twoclinical applications. The first is for parenteral or intravenousnutrition, as a source of fat calories and essential fatty acids.Examples include Intralipid®, available from Pharmacia and Upjohn andLiposyn®, available from Abbott Laboratories. Emulsions are also beingused as a vehicle for poorly water-soluble lipophilic drugs that cannotbe injected directly. Examples include Diprivan®, containing theanesthetic drug propofol, and Diazemuls®, containing the drug diazepam.

Lipid emulsions are inherently unstable. No commercially available lipidemulsion is stable following dilution in physiological (0.9% w/v) saltsolution. This instability is manifested by formation of large dropletsof non-emulsified oil on the surface as well as by a shift in dropletsize distribution towards much larger diameters. Such changes oftenoccur within the first hour following dilution in saline and areaccelerated by heating or by applying any shear force. The relativelylow pH and high ionic strength of saline contributes to this effect.

Commercial lipid emulsions separate into oil and water layers uponthawing after storage at freezing temperatures. For this reason, specialcare must be taken when shipping in winter through geographic areashaving below freezing temperatures. It is preferred that the lubricantbe an emulsion which is stable in saline and stable upon freezing withsubsequent thawing. The present invention meets these needs andovercomes other deficiencies in the prior art.

What would be desirable is an improved, pharmacologically compatiblemedical lubricant. What has not been provided is an injectable medicallubricant suitable for lubricating rotating and otherwise moving medicaldevices.

SUMMARY OF THE INVENTION

present invention includes a medical lubricant suitable for injectioninto a patient. The lubricant is an oil-in-water emulsion including anoil, a surfactant, a co-surfactant and water. The lubricant preferablyalso includes a cryogenic agent, a pH buffer, and a preservative. Thelipid emulsion preferably has a mean particle or droplet diameter ofless then 1 micrometer, most preferably less than about 0.5 micrometer.The lubricant can be subjected to substantial shear by a rotatingmember, exhibits a commercially acceptable shelf life during storageunder ambient temperatures, and is able to withstand freeze-thaw cycleswithout substantial degradation. The lubricant can be diluted inphysiological saline for injection and maintains suitable emulsiondroplet size after such dilution.

The oil can be a vegetable oil or a medium chain triglyceride. Thepreferred oil is refined olive oil, which preferably comprises mostlymono-unsaturated oleic acid. The oil can lubricate medical devices suchas rotating drive shafts in atherectomy devices, thereby reducing wearon moving parts. A mean droplet size of less than about 1 micrometerallows injection into the bloodstream and subsequent absorption by thebody without ill effect. The emulsion most preferably includes about 20g refined olive oil per 100 mL emulsion.

The surfactant can be a phospholipid, preferably purified egg yolkphospholipids. The surfactant stabilizes the oil droplets dispersed inthe continuous aqueous phase. The present invention preferably includesabout 1.2 g egg yolk phospholipids per 100 mL emulsion.

The co-surfactant can be a salt of a bile acid, most preferably sodiumdeoxycholate. The co-surfactant significantly improves droplet stabilityafter saline dilution, heating, and exposure to high shear forces.Droplet stability includes the resistance to formation of largerdroplets, creaming, and formation of a separate oil layer. Bile salt,acting in conjunction with glycerin, provides improved freeze-thawstability. Applicants believe the bile salt also improves lubricity byacting as a wetting agent, improving the coating of moving metal parts.The present invention most preferably includes about 0.4 g bile salt per100 mL emulsion.

The cryogenic agent can be refined propylene glycol or glycerin,preferably glycerin. Glycerin also provides improved lubricity. Thepresent invention preferably includes about 10 g glycerin per 100 mLemulsion.

The pH buffer is preferably an amino acid buffer. The pH buffer impartsimproved droplet stability in a saline diluent. The amino acid buffer ismost preferably L-histidine in a concentration of about 0.16 g per 100mL emulsion.

The preservative is preferably a heavy metal chelator such as disodiumEDTA. EDTA, and the histidine buffer, serve as antioxidants, protectingunsaturated fatty acids found in egg yolk phospholipids. Theantioxidants provide an extended shelf life for the emulsion at roomtemperature and inhibit peroxide formation during clinical use. DisodiumEDTA is preferably present in about 0.014 g per 100 mL emulsion.

The emulsion preferably has the pH adjusted to between about 8.3 and 8.8with a base such as sodium hydroxide. This pH range optimizes theemulsion stability in the presence of non-buffered saline, which isslightly acidic. Sodium hydroxide can be present in about 3.0 mEq perliter of emulsion.

An emulsion according to the present invention can be prepared bycombining refined olive oil, 1.2% egg yolk phospholipid, 0.16%L-histidine (10 mM), 0.014% disodium EDTA (0.5 mM), and water, followedby ultrasonic processing for about 15 minutes. The emulsion can also beprepared using high pressure homogenization techniques well known tothose skilled in the art.

In use, the emulsion can be stored for at least 18 months, preferablytwenty-four (24) months at room temperature. The emulsion can be storedfrozen at minus 30 degrees C, and then thawed without causingsignificant changes in droplet size distribution. The emulsion can beadded to normal, unbuffered 0.9% saline solution. One anticipated use isinjection of the emulsion into an IV bag of saline, thereby diluting theemulsion. The diluted emulsion can be infused from the IV bag through acatheter tube housing a rotating member such as an atherectomy driveshaft or an ultrasonic probe drive shaft. The emulsion serves tolubricate the moving parts and can thereafter enter the blood stream ofa patient without ill effect.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In a preferred embodiment of the invention, the oil-in-water emulsionlubricant comprises a mixture of water, oil, a surfactant, aco-surfactant, a phospholipid, a cryogenic agent, a pH buffer and apreservative.

Preferably the oil used in the lipid emulsion lubricant is a liquid atroom temperature, most preferably olive oil. Chemically, olive oilcontains mostly mono-unsaturated oleic acid. Different oil bases, suchas either soybean oil, which contains a mixture of polyunsaturated fattyacids, mainly C₁₄, C₁₆ and C₁₈, or medium chain triglycerides (MCT) mayalso be used, especially with varying concentrations of the otheringredients and with different surfactants. Almond oil, coconut oil,corn oil, cotton seed oil, marine oil, palm kernel oil, peanut oil,safflower oil, sesame oil, sunflower oil, and physical orinteresterified mixtures thereof can also be used. These other oilbases, however, are not as effective as olive oil. Quite surprisingly,we found that olive oil emulsions lubricate better than soybean oilemulsions. The lubricant reduces wear on moving components. In apreferred embodiment of the invention, the concentration of olive oil inthe lubricant is from about 5 to about 40 g/100 mL emulsion, morepreferably about 15 to about 25 g/100 mL emulsion, and is mostpreferably about 20 g/100 mL emulsion.

An emulsion is a dispersion of one immiscible liquid within another,commonly oil-in-water. An emulsifier is a surface active agent designedto coat and stabilize the dispersed droplets against coalescence.However, in certain formulations, this dispersion is insufficientlystabilized by the primary emulsifier which is typically added atconcentrations of about 1-5% w/v. In such cases, a second surface activeagent, known as a co-surfactant, may be added. A co-surfactant istypically used at a fractional concentration of the primary emulsifier,e.g., 0.1-1.0%. In principle, co-surfactants are added to accomplishspecific tasks such as enhancing electrostatic surface charge on thedispersed droplets or strengthening the interfacial film between oil andwater. In reality, it is quite difficult to predict in advance whichco-surfactant, if any, will stabilize a novel emulsion formulation underspecific environmental conditions.

A primary emulsifier in the lipid emulsion lubricant could, for example,be selected from a group of phospholipids such as soy bean or egg yolkphospholipids. A preferred phospholipid is egg yolk phospholipid,preferably present in a concentration of about 0.3 to about 3 g/100 mLemulsion, more preferably about 0.6 to about 1.8 g/100 mL emulsion, mostpreferably about 1.2 g/100 mL emulsion.

The co-surfactant could be, for example, PEG-400 (polyethylene glycol),Pluronic F68 (a nonionic, polyoxethylene-polyoxypropylene blockcopolymer, BASF), dimyristyl phosphatidyl glycerin (DMPG), or the saltof a bile acid. When PEG-400 is used, it can be present at about 5%,weight/volume. When Pluronic F68 is used, it can be present at about 1%,weight/volume. Preferably, the co-surfactant is the salt of a bile acidsuch as cholic acid, deoxycholic acid, taurocholic acid or mixturesthereof. Most preferably, the co-surfactant is sodium deoxycholate, asit is somewhat more effective in reducing wear than DMPG. In the presentinvention, the superiority of sodium deoxycholate over other testedco-surfactants was unexpected and unpredicted. In a preferredembodiment, sodium deoxycholate is present at a concentration of about0.04 to about 4 g/100 mL emulsion, more preferably about 0.2 to about0.8 g/100 mL emulsion, most preferably about 0.4 g/100 mL emulsion.

A preferred cryogenic agent is refined propylene glycol or glycerin,most preferably glycerin. Glycerin serves to provide freeze toleranceand improves the overall lubricating properties of the emulsion.Glycerin is preferably present at a concentration of about 1 to about 30g/100 mL emulsion, more preferably about 2 to about 20 g/100 mLemulsion, most preferably about 10 g/100 mL emulsion.

A preferred pH buffer is an amino acid buffer, for example, alanine,aspartic acid, glycine, histidine, isoleucine, leucine, methionine,phenylalanine, proline, serine, valine or mixtures thereof. A preferredamino acid buffer is histidine. Histidine contributes significant pHbuffering capacity in the critical pH 6 to 8 range, having a pK_(a) ofabout 6.0. This pH buffering contributes to emulsion stability afterdilution in saline. In addition, histidine serves as an antioxidant,specifically a hydroxy radical scavenger. Histidine is preferablypresent at a concentration of about 0.01 to about 1 g/100 mL emulsion,more preferably about 0.05 to about 0.3 g/100 mL emulsion, mostpreferably about 0.16 g/100 mL emulsion.

A preferred preservative is a heavy metal chelator such as disodiumEDTA. The combination of EDTA and histidine serves as a potentantioxidant to protect unsaturated fatty acids found in egg yolkphospholipids. This antioxidant system serves both to protect theemulsion in the bottle during prolonged storage at room temperature aswell as to inhibit peroxide formation during clinical use. Disodium EDTAis preferably present at a concentration of about 0.001 to about 0.1g/100 mL emulsion, more preferably about 0.01 to about 0.05 g/100 mLemulsion, most preferably about 0.014 g/100 mL emulsion.

Finally, sodium hydroxide can be added to titrate the emulsion to afinal pH of about 8.3 to about 8.8. This pH range is chosen to optimizeemulsion stability in the presence of non-buffered saline which isslightly acidic.

In order to manufacture the present invention, a mixture ofwater-for-injection with the ingredients listed above in the amountsdescribed can be passed through a high pressure homogenizer. Theresulting mixture is an opaque white, milky liquid that is a suspensionof small oil droplets in water, with a normal droplet size distribution.The droplet size has a mean of about 0.4 μm and a maximum of about 4 μm.The distribution includes 90% of droplets less than about 0.65μm andless than 0.5% of droplets greater than 1m. Even after experiencing highshear, all droplets remain less than about 5 μm.

The lubricant is to be shipped in sterile vials and injected into asterile saline intravenous (IV) bag prior to use. During a rotationalatherectomy procedure, the lubricant can be infused through the catheterof a Rotablator® system and then into the coronary artery. Because thepresent invention is safe for parenteral use, it is a potentiallubricant for any device operating inside the human body. Examples ofthis are: interoperative milk into which endoscopic equipment is dippedbefore placement into the human body; coating for sutures in order toreduce friction; lubricant for heart valves in order to ease placementduring surgery; lubricant for ultrasonic catheters; and lubricant forother future devices that employ swiftly-moving parts within the body.

EXPERIMENTAL RESULTS Sample Preparation

Four one-liter lots of 20% olive oil emulsion were prepared, with each100 mL of emulsion containing: 20.0 g olive oil, 1.2 g egg yolkphospholipid (a surfactant), 0.40 g sodium deoxycholate (a bile saltco-surfactant), 0.16 g L-histidine (an amino acid pH buffer), and 0.014g disodium EDTA (a preservative). 3.0 mEq/L NaOH was also added toadjust pH. The four lots varied only in glycerin content (a cryogenicagent) in the amounts specified in Table 1. Intralipid, a commerciallyavailable lipid emulsion for parenteral nutrition, is included in Table1 for comparison. Intralipid 20% contains 20% w/v soybean oil, egg yolkphospholipids, glycerin, sodium hydroxide, and water for injection(WFI).

                  TABLE 1                                                         ______________________________________                                        Glycerin Concentration, Osmolality and Zeta Potential                                   Glycerin Conc.,                                                                            Osmolality,                                                                              Zeta                                        Lot Number                                                                              Grams/100 mL mOsm/kg    Potential, mv                               ______________________________________                                        Intralipid 20%                                                                          2.25          350*      -38                                         HT-049    1.6          280        -46                                         HT-050    10.0         300        -48                                         HT-051    20.0         322        -44                                         HT-052    30.0         346        -40                                         ______________________________________                                         *undiluted sample                                                        

High glycerin concentrations are expected to elevate osmolality anddepress the freezing point. The original formulation was designed with1.6% glycerin to produce an isotonic product, having about 280-320mOsm/kg. As osmolality could not be measured directly in higherconcentration glycerin samples using the freezing point depressionmethod, osmolality was measured after a 1:50 dilution in 0.9% saline.This dilution was chosen to represent expected clinical practice. Theosmolality of the Intralipid was measured on an undiluted sample.

The Zeta potential or net surface charge is an important determinant ofstability in colloidal systems. Zeta was calculated frommicroelectrophoretic mobility in 5 mM Hepes buffer at pH 8.0 using alaser light scattering detection system (Malvern ZetaSizer). Control(non-frozen) samples were used. As can be seen in Table 1, Zetapotential was most negative at about 10% glycerin concentration.

Visual Inspection

At least three separate bottles from each lot were visually inspectedfor homogeneity and surface oil. Inspections were performed on initialsamples about one week after sterilization and on samples that had beensubjected to freeze/thaw and shipping. "Creaming" refers to the rapidfloatation (e.g., within an hour) of large, emulsified oil dropletsformed either by coalescence or by aggregation of smaller emulsifieddroplets. In contrast, surface oil ("free oil") droplets are notemulsified. The results of visual inspection are summarized in Table 2.As can be seen in Table 2, Lot HT-050, having 10% glycerin, had nosurface oil and no creaming, either initially or after the freeze/thawcycle.

                  TABLE 2                                                         ______________________________________                                        Visual Examination                                                                    Initial        Post Freeze/Thaw                                       Lot No. (non-frozen)   (all temperatures)                                     ______________________________________                                        HT-049  no surface oil; no                                                                           no surface oil; rapid                                          creaming       formation of cream layer                               HT-050  no surface oil; no                                                                           no surface oil; no creaming                                    creaming                                                              HT-051  a few oil droplets                                                                           a few oil droplets (≦1 mm);                             (≦1 mm); no creaming                                                                  no creaming                                            HT-052  no surface oil; no                                                                           no surface oil; no creaming                                    creaming                                                              ______________________________________                                    

Freeze/Thaw and Stress Testing

Measurements of pH and droplet size were performed on triplicate samplesfrom each lot. Test samples were subject to freeze/thaw and shipping.Control samples were subjected to no freezing, only shipping. Bothcontrol and freeze/thaw samples were subjected to a saline/heat/shearstress test. This test involves a 1:20 dilution in 0.9% saline, followedby heating in a 40 degree C water bath for 5 minutes, and ending with 3minute high-shear processing by a rotor-stator device (Ultra Turrax,20,500 rpm) at 40 degree C. Due to significant deterioration (creaming),freeze/thaw samples from Lot HT-049 (1.6 % glycerin) were not subjectedto this test. Some of the data for Intralipid 20% and Lot HT-050 (10%glycerin) are summarized in Table 3.

Table 3 contains the results: pH (before and after freeze/thaw for LotHT-050); pH after dilution/heat/shear; mean droplet diameter before andafter dilution/heat/shear; droplet diameter for which 90% of thedroplets have a smaller diameter before and after dilution/heat/shear;droplet diameter for which 100% of the droplets have a smaller diameterbefore and after dilution/heat/shear; and the percent of droplets havinga droplet diameter greater than 1 micrometer before and afterdilution/heat/shear.

Inspection of Table 3 shows a significant increase in droplet diameterafter dilution/heat/shear stress for Intralipid 20%. As previouslydiscussed, freeze/thaw of Intralipid 20% results in phase separation.Lot HT-050 (10% glycerin) in the control (before freeze/thaw) shows avery slight increase in droplet diameter at the 90th percentile and amaximum droplet size of 4.30 micrometers due to dilution/heat/shear.This compares with an Intralipid increase from 0.80 to 1.23 micrometersdroplet diameter at the 90th percentile and maximum droplet size of 12.2micrometers due to dilution/hear/shear. Freeze/thaw had an insignificanteffect on droplet size for the Lot HT-050 sample. Freeze/thaw also hadno significant change on the effects of dilution/heat/shear on theHT-050 sample after thawing.

                                      TABLE 3                                     __________________________________________________________________________    Effects of Freeze/Thaw and Heat/Shear                                         on 20% Olive Oil Emulsions                                                                      Heat/   Heat/   Heat/                                       Lot No./  Heat/                                                                             Mean                                                                              Shear   Shear   Shear    Heat/                              Storage   Shear                                                                             Dia,                                                                              Mean                                                                              90% <                                                                             90% <                                                                             100% <                                                                            100% <                                                                            % <  Shear % <                          Condition                                                                           pH  pH  μm                                                                             Dia μm                                                                             μm                                                                             μm                                                                             μm                                                                             1 μm                                                                            1 μm                            __________________________________________________________________________    Intralipid                                                                          7.85                                                                              6.70                                                                              0.49                                                                              0.67                                                                              0.80                                                                              1.23                                                                              3.49                                                                              12.2                                                                              4.6  13.9                               20%/                                                                          Control                                                                       50/   8.63                                                                              7.42                                                                              0.40                                                                              0.42                                                                              0.61                                                                              0.65                                                                              1.51                                                                              4.30                                                                              0.50 3.2                                Control                                                                       50/   8.64                                                                              7.54                                                                              0.40                                                                              0.41                                                                              0.61                                                                              0.64                                                                              1.51                                                                              4.30                                                                              0.50 2.6                                Frozen @                                                                      -30° C.                                                                __________________________________________________________________________

Phase-Contrast Microscopy

The samples were also observed under phase-contrast microscopy.Freeze/thaw samples from ET-049 (1.6% glycerin) showed a very largenumber of coalesced and aggregated oil droplets. In contrast, allelevated glycerin samples, HT-050 (10% glycerin), HT-051 (20% glycerin),and HT-052 (30% glycerin) had a very uniform, clean appearance with nolarge droplets. Samples were also observed after the saline/heat/shearstress test. Samples from all olive oil lots looked excellent, while theIntralipid samples showed many large coalesced droplets. Theseobservations are consistent with the drop size distribution data shownin Table 3.

Sample Test Summary

The addition of glycerin at 10% weight/volume appears sufficient toprotect the olive oil emulsions from freeze/thaw damage for at least 48hours, even at minus 30 degrees C. In this respect, no advantages wereseen with higher concentrations of glycerin. The presence of elevatedglycerin concentration had no significant effect on product appearance,pH, drop size distribution or Zeta potential. In contrast, the 1.6%glycerin sample (HT-049) exhibited severe creaming followingfreeze/thaw. The complete preservation of emulsion quality duringfreeze/thaw using only 10% w/v glycerin (e.g., lot #HT-50) was quitesurprising and unexpected. Since samples stored at -30° C. appear to befrozen solid, glycerin is not acting as a simple antifreeze agent.Cryopreservation must be occurring by an action at the oil-waterinterface of the dispersed droplets, i.e., in the phospholipidmonolayer.

The addition of each 10% of glycerin, after a 50-fold dilution in 0.9%saline, adds about a 20 mOsm/kg increment in osmolality. Thus, even a30% glycerin emulsion has a diluted osmolality no higher than undilutedIntralipid 20%. Therefore no tonicity problems are expected in clinicalapplications.

Utility

The utility of the invention was tested using the Rotoblator system.This system rotates a 135 cm stainless steel drive coil with an attacheddiamond coated burr over a 0.009 inch diameter stainless steel guidewire at 180,000 rpm. The system in current use is lubricated duringstartup with a thin film of HYSTRENE on the guide wire and throughoutthe operation by a continuous infusion of normal saline. This allows forefficient operation for only limited duration, as the lubricant washesaway and is not replenished, therefore the performance can start todegrade as the device starts operating. Performance degradation can takethe form of loss of speed, heat build-up, guide wire wear, drive coilwear, burr wear and reduced axial mobility.

Optimally, for use with the Rotoblater Advancer/guide wire system, thelubricant should withstand high shear stress at 50° C. without emulsiondegradation. All emulsion droplets should remain less than 5 micrometersin diameter, even after shear stress associated with use of this device.In addition, a mixture of the emulsion in saline should remain stableafter overnight storage at room temperature and be non-toxic.

Wear and Speed Stability Test

Lubricants were tested using the Rotoblater advancer. An advancer havinga 1.75 mm burr was passed through a PTFE tube with a 2.2 mm ID which iswrapped over a pair of mandrels to create a fixed "S" shaped path. Theguide wire distal end is placed about 2 inches past the burr and thefixture immersed in a 37° C. waterbath and run for 5 minutes. Thelubricants tested included both normal saline and saline mixed with 20cc per liter of the olive oil emulsion. The advancer speed was recordedand the wear scars on the guide wire wear measured with a LaserMicrometer. With saline alone, average wear was 0.0048 inch comparedwith only 0.0001 inch wear for saline with the emulsion added. Withsaline alone, the average speed change was a decrease of 13877 rpm,compared with an average increase of 79 rpm for saline with the emulsionadded. Thus, both guide wire wear and speed stability improved with theemulsion added.

Tortuous Advance Force Test

Another series of tests was performed, similar to the previous study buthaving a more tortuous path, to simulate the path of a coronary vessel.The burr was advanced and retracted over an "S" shaped bend throughoutthe 5 minute test. The test measured the force required to advance andretract the burr, the advancer speed, and the fluid temperaturedownstream of the burr in the PTFE tube. With saline alone, the rpmdecreased by 13,000 rpm compared with an increase of 800 rpm for salinewith emulsion. With saline alone, the peak fluid temperature was 58degrees C compared with 47.5 degrees C for saline with emulsion. Withsaline alone, 170 gm of force was required at the peak to advance thedevice, compared with 120 gm for saline with emulsion. Thus, theemulsion provided improved lubrication over saline alone.

Comparison with Other Lipid Emulsions

Another study was performed using stainless steel rods with surfacespeeds and pressures similar to those found in the Rotoblater. A seriesof emulsions of olive oil and Intralipid was tested for wear resistanceand emulsion stability. The average wear scars using Intralipid were 64millionths of an inch +/-16, compared to only 5 millionths of an inch+/-11 for olive oil emulsions. Furthermore, the olive oil emulsionshowed insignificant post shear changes in droplet size distribution,the mean droplet diameter remaining about 0.4 micrometers. In distinctcontrast, the Intralipid lubricant showed a dramatic degradation in theemulsion, including an increase in maximum droplet diameter to about 10micrometers, an increase in mean droplet diameter to about 0.8micrometers, an increase in 90th percentile droplet diameter from about0.8 micrometers to about 2 micrometers, and a bimodal distribution indroplet diameter, having a second peak at about 2 micrometers.

Oil Emulsions Comparison Tests

A series of oil emulsion samples was prepared, all containing 20%weight/volume oil, 1.2% egg yolk phospholipid, 0.16% L-histidine (10mM), and 0.014% disodium EDTA (0.5 mM). Additional excipients in eachsample are indicated in Table 4. Emulsions were prepared by ultrasonicprocessing (Sonics and Materials Inc., 13 mm horn, 200 mL sample volume,and 80% power for 15 minutes at 50% duty cycle). Drop size distributionwas determined by laser light scattering (Malvern MasterSizer).Stainless steel wear testing was expressed as a ratio of stainless steelvolume lost with a saline control divided by the volume lost with thetest emulsion. Higher ratios indicate less steel lost and thereforebetter lubrication.

                  TABLE 4                                                         ______________________________________                                        Olive Oil-in-Water Emulsion is Most                                           Effective for Lubrication                                                                                               Stainless                                                                     Steel                                    Oil      Aqueous                     Wear,                               Prep Phase,   Additive Sterile                                                                             Mean         Saline                              No.  20% w/v  % w/v    pH    Dia, μm                                                                          % > 1 μm                                                                          Emulsion                            ______________________________________                                        1    MCT      none     8.14  1.10  18.4   1.09                                2    MCT      glycerin 8.25  0.95  16.8   1.56                                              2.25%                                                           3    MCT      PEG-400, 8.21  0.87  18.8   0.95                                              5.0%                                                            4    MCT      Pluronic 8.24  0.49  4.2    1.88                                              F68,                                                                          1.0%                                                            10   15% MCT  None     8.11  0.75  18.4   2.53                                     5%                                                                            Castor                                                                        Oil                                                                      6    Olive    none     8.20  0.65  13.0   23.71                               9    SBO      none     8.25  0.81  25.6   7.12                                ______________________________________                                    

As can be seen from inspection of Table 4, there was a dramatic andunexpected advantage with respect to lubrication I-efficiency usingpurified olive oil (Croda) as the emulsified lipid phase versus otheroils such as MCT (medium chain triglycerides). Other studies (not shown)confirmed the superiority of olive oil.

Co-surfactant Emulsion Stability Test

In order to be useful as a lubricant emulsion, the injectable productmust be stable for several hours after dilution in unbuffered, normal,0.9% saline solution. Therefore, a series of samples having variousaqueous co-surfactants was tested in a 20% olive oil emulsion. Thesamples included a control having no co-surfactant, PEG-400 added at 5%,Pluronic F68 (nonionic block copolymer) added at 1%, sodium deoxycholate(a bile salt) added at 0.2%, and Intralipid 20%. The emulsions werediluted 1:20 in 0.9% saline and allowed to stand overnight at roomtemperature. Emulsion quality was scored by monitoring the formation oflarge droplets (% >1 micrometer) using a laser light scatteringinstrument. In decreasing order of the percentage of droplets having adiameter greater than 1 micrometer, Intralipid had 60%, Pluronic F6842%, PEG-400 37%, control 25%, and deoxycholate 6%. From severalexperiments such as this, we concluded that the use of deoxycholate as aco-surfactant best protects this olive oil emulsion following salinedilution.

Diluted Intralipid Droplet Size Tests

Intralipid was evaluated for use as a lubricant in a stainless steelwear test. Intralipid was evaluated after dilution in Water ForInjection (WFI), after dilution 1:20 in saline, and after dilution insaline with heat/shear stress. The initial Intralipid mean dropletdiameter after dilution in WFI was 0.44 micrometer, compared with 2.07after dilution in saline and 0.96 after dilution in saline withheat/shear stress. The initial percentage of droplets greater than 1micrometer in diameter was 2.6%, compared with 42.8% after dilution insaline and 26.1% after dilution in saline with heat/shear stress. WhileIntralipid is a safe and clinically acceptable intravenous nutritionproduct, it is not useful as an injectable lubricant because thissoybean oil emulsion shows large oil droplets and creaming followingsaline dilution/heat/shear stress.

Co-surfactant Saline Dilution/Heat/Shear Stress Tests

The percentage of large (greater than 1 micrometer) droplets, bothinitially and after saline dilution/heat/stress testing, was measuredfor emulsions having a series of co-surfactants.Dimyristoylphosphatidylglycerin (DMPG), a charged lipid, was added at0.2%. Poloxamer 331, a lipophilic, non-ionic block copolymer, as addedalong with DMPG in another sample. Deoxycholate, a bile acid, was addedat 0.4%. Poloxamer 331 was added along with deoxycholate in anothersample. Intralipid was also tested.

The DMPG preparation initially had about 37% of droplets with a diametergreater than 1 micrometer, deoxycholate about 14%,poloxamer/deoxycholate and Intralipid about 3%, and poloxamer/DMPG about2%. The failure of DMPG to cause smaller droplet size was unexpectedsince this lipid enhances the stabilizing electronegative surface chargeon dispersed droplets.

After saline dilution/heat/stress testing, however, DMPG had about 37%of droplets with a diameter greater than 1 micrometer,poloxamer/deoxycholate about 32%, Intralipid and poloxamer/DMPG about27% and deoxycholate about 15%. Thus, while some co-surfactants providea finer initial droplet size distribution than deoxycholate, theyprovide much less protection against saline dilution/heat/shear stress.From studies such as these, we concluded that sodium deoxycholate is themost preferred co-surfactant.

Numerous characteristics and advantages of the invention covered by thisdocument have been set forth in the foregoing description. It will beunderstood, however, that this disclosure is, in many respects, onlyillustrative. The scope of this invention is, of course, defined in thelanguage in which the appended claims are expressed.

What is claimed is:
 1. A method of lubricating a medical devicecomprising:introducing a medical lubricant lipid emulsion into a patientduring treatment of the patient with a medical device wherein saidmedical device has a moving part that is operative inside the patient,and contacting said moving part inside the patient with said medicallubricant, said medical lubricant comprising:a lipid; a surfactant; aco-surfactant; and water.
 2. The method of claim 1, wherein the medicallubricant further comprises a pH buffer.
 3. The method of claim 1,wherein the medical device is selected from the group consisting of anatherectomy device, an angioplasty devise, a cardiac assist device, anultrasonic catheter, a minimally invasive surgical devise and a heartvalve.
 4. The method of claim 2, further comprising diluting the medicallubricant up to two hundred-fold with a suitable solution prior tointravenous infusion.
 5. The method of claim 4, further comprisinginfusing the diluted medical lubricant through a catheter or a catheterhousing the medical device.
 6. The method of claim 1, wherein the lipidis refined olive oil, the surfactant is egg yolk phospholipid, theco-surfactant is sodium deoxycholate, and the medical lubricant furthercomprises:glycerin; L-histidine; disodium ethylenediamine tetraceticacid (EDTA); and sodium hydroxide.
 7. The method of claim 6, wherein themedical device is selected from the group consisting of an atherectomydevice, an angioplasty devise, a cardiac assist device, an ultrasoniccatheter, a minimally invasive surgical devise and a heart valve.
 8. Themethod of claim 6, further comprising diluting the medical lubricant upto two hundred-fold with a suitable solution prior to intravenousinfusion.
 9. The method of claim 8, further comprising infusing thediluted medical lubricant through a catheter or a catheter housing themedical device.
 10. A method of lubricating a medical devicecomprising:coating a medical device prior to use in a patient with amedical lubricant, said medical lubricant comprising:a lipid; asurfactant; a co-surfactant; and water, wherein the medical device isselected from the group consisting of a suture material, an endoscopicinstrument, an atherectomy device, an angioplasty device, a cardiacassist device, an ultrasonic catheter, a minimally invasive surgicaldevice and a heart valve.
 11. The method of claim 10, wherein the lipidis refined olive oil, the surfactant is egg yolk phospholipid, theco-surfactant is sodium deoxycholate, and the medical lubricant furthercomprises:lubricant further comprises:glycerin; L-histidine; disodiumethylenediamine tetracetic acid (EDTA); and sodium hydroxide.
 12. Amethod of lubricating an intravascular device comprising:preparing apatient for atherectomy; inserting into the patient an intravasculardevice, said intravascular device capable of differentially removingintravascular deposits from the walls of an artery; infusing a medicallubricant into the patient during said insertion or during operation ofsaid intravascular device, said medical lubricant oil emulsioncomprising:olive oil; an egg yolk phospholipid; a bile salt; an aminoacid buffer; and water.
 13. The method of claim 12 wherein saidintravascular device is a rotational atherectomy device.
 14. The methodof claim 12, wherein the medical lubricant oil emulsion furthercomprises:a cryogenic agent; a heavy metal chelating agent; and a pHadjusting base.
 15. The method of claim 14, wherein said olive oil has aconcentration of between about 5 and about 40 g/100 mL emulsion, saidegg yolk phospholipid has a concentration of between about 0.3 and about3 g/100 mL emulsion, said bile salt has a concentration of between about0.04 and about 4.0 g/l 100 mL emulsion, said cryogenic agent has aconcentration between about 1 and about 30 g/100 mL emulsion, said aminoacid buffer has a concentration between about 0.01 and about 1 g/100 mLemulsion, said chelating agent is disodium EDTA having a concentrationbetween about 0.005 and about 0.05 g/100 mL emulsion, said pH adjustingbase is sodium hydroxide and the pH is adjusted to a pH between about8.3 and 8.8, and said medical emulsion has a mean droplet size of lessthan about 5 micro meters.
 16. The method of claim 15, wherein saidintravascular device is a rotational atherectomy device.